Metabolomics Based Prediction of Delayed Effects of Acute Radiation Exposure

摘要 由于辐射事故或核恐怖主义，受害者暴露于电离辐射， 辐射综合症由于一些努力已经导致了针对这些疾病的医学对策的发展， 由于急性辐射毒性，受害者在辐射事件中幸存的机会大大增加。 然而，在急性效应中幸存的受害者中，将有数月至数十年的潜伏期， 迟来的伤害晚期器官损伤是进行性不可逆的，对生活质量产生不利影响， 会危及生命因此，先发制人地识别有这种迟发效应风险的个人至关重要， 决策过程，以确定最合适的干预策略的时机和选择。 基于代谢组学的生物标志物测定在各种疾病的临床转化中迅速获得信任 设置.我们的初步研究强烈表明，从高分辨率质谱获得的多分析物谱 光谱分析平台提供了具有高转化值辐射损伤的可靠和早期指标。在这 I期研究，采用发现-验证研究设计，我们建议确定预期代谢 放射损伤的生物标志物对两个主要器官有延迟并发症的风险：心脏和大脑。最初我们 将利用小鼠模型的γ射线暴露，以确定血浆和尿液的生物标志物，预测程度 在临床症状出现之前，心脏和大脑就会出现损伤。我们不仅会发现新的 生物标志物，而且在独立的小鼠队列中验证它们。我们将确定哪种基质（血浆或 尿）为每个器官系统提供了最佳的预测因子（技术目的1）。后续我们将 验证从暴露于γ-氨基丁酸的男性和女性NHP获得的血浆和尿液样品中的这些生物标志物。 放射和长期随访器官损伤和生存结局（技术目标2）。FDA指南 将遵循生物标志物开发和共同开发，以确保考虑监管因素 在这个过程中的所有步骤中。这一研究领域的大多数研究鉴定了尿液或血浆代谢物 在辐射后96小时内测量时，区分辐射和未辐射动物。 虽然这种方法在确定一个人暴露于哪种辐射剂量方面有价值，但它不能预测 延迟辐射损伤的风险该项目将填补这一空白，并成为第一批 鉴定和验证迟发性辐射损伤的生物标志物组。成功完成技术目标 将能够选择生物标志物组，这些生物标志物组将准备用于基于试剂盒的测定的分析验证 在随后的第二阶段应用中。总之，这些研究最终将使发展 一种商业上可行的基于试剂盒的伴随诊断测试，其可用于识别处于以下风险中的个体： 因为辐射而造成迟发性损伤

Abstract Exposure of victims to ionizing radiation due to a radiological accident or nuclear terrorism leads to the acute radiation syndrome. Since several efforts have led to the development of medical countermeasures against these acute radiation toxicities, the chance that victims survive a radiological event has significantly increased. However, in victims who survive the acute effects, there will be a latent period of months to decades before delayed injuries manifest. Late organ injury is progressively irreversible, adversely affects quality of life and may prove life-threatening. Therefore, pre-emptive identification of individuals at risk for such late effects is critical in the decision process to determine the timing and choice of the most appropriate intervention strategies. Metabolomics-based biomarker assays are fast gaining credence for clinical translation in a variety of disease settings. Our preliminary studies strongly suggest that multi-analyte profiles obtained from a high-resolution mass spectrometry platform provide robust and early indicators of radiation injury with high translational value. In this Phase I study, using a discovery-validation study design, we propose to identify anticipatory metabolic biomarkers of radiation injury to two major organs at risk for delayed complications: heart and brain. Initially, we will make use of murine models of γ-ray exposure to identify plasma and urine biomarkers that predict the extent of injury that will manifest in the heart and brain before clinical symptoms appear. We will not only discover new biomarkers, but also validate them in independent cohorts of mice. We will determine which matrix (plasma or urine) provides the best predictor for each of the organ systems (Technical Objective 1). Subsequently, we will validate these biomarkers in plasma and urine samples obtained from male and female NHPs exposed to γ- radiation and followed up long term for organ injury and survival outcomes (Technical Objective 2). FDA guidance on biomarker development and co-development will be followed to ensure regulatory considerations are taken into account at all steps in the process. Most studies in this area of research identify urine or plasma metabolites that differentiate between irradiated and unirradiated animals when measured within 96 hours after radiation. While this approach has value in determining which radiation dose one was exposed to, it does not predict someone’s risk for developing delayed radiation injuries. This project will fill this gap and be among the first to identify and validate biomarker panels of delayed radiation injuries. Successful completion of technical objectives will enable the selection of biomarker panels that would be ready for analytical validation for a kit-based assay in a subsequent Phase II application. Taken together, these studies, ultimately, will enable the development of a commercially viable kit based companion diagnostic test that can be used for identifying individuals at risk for developing delayed injuries from radiation exposure.